期刊
NEUROBIOLOGY OF DISEASE
卷 70, 期 -, 页码 53-68出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2014.06.006
关键词
CDKL5 disorder; Rett's syndrome; Neurodevelopmental disorders; Neurogenesis impairment; Dendritic development; AKT/GSK-3 beta signaling
资金
- Telethon grant [GGP11147]
- CDKL5 associazione di volontariato
- International Foundation for CDKL5 Research (IFCR)
- ISRF
- EMBL
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a neurodevelopmental disorder characterized by early-onset intractable seizures, severe developmental delay, intellectual disability, and Rett's syndrome-like features. Since the physiological functions of CDKL5 still need to be elucidated, in the current study we took advantage of a new Cdk15 knockout (KO) mouse model in order to shed light on the role of this gene in brain development. We mainly focused on the hippocampal dentate gyrus, a region that largely develops postnatally and plays a key role in learning and memory. Looking at the process of neurogenesis, we found a higher proliferation rate of neural precursors in Cdk15 MO mice in comparison with wild type mice. However, there was an increase in apoptotic cell death of postmitotic granule neuron precursors, with a reduction in total number of granule cells. Looking at dendritic development, we found that in Cdk15 MO mice the newly-generated granule cells exhibited a severe dendritic hypotrophy. In parallel, these neurodevelopmental defects were associated with impairment of hippocampus-dependent memory. Looking at the mechanisms whereby CDKL5 exerts its functions, we identified a central role of the AKT/GSK-3 beta signaling pathway. Overall our findings highlight a critical role of CDML5 in the fundamental processes of brain development, namely neuronal precursor proliferation, survival and maturation. This evidence lays the basis for a better understanding of the neurological phenotype in patients carrying mutations in the CDKL5 gene. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
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